rs45604036

Variant names:

• chr14-45176512-A-G
• rs45604036
• NM_020937.4:c.3758A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-45176512-A-G
• chr14-45176512-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020937.4(FANCM):​c.3758A>G​(p.Asn1253Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,604,822 control chromosomes in the GnomAD database, including 812 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1253D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (64 hom., cov: 32)
  • Exomes 𝑓: 0.030 (748 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.196
• Publications: 13 publications found

Genes affected

FANCM (HGNC:23168): (FA complementation group M) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group M. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

FANCM Gene-Disease associations (from GenCC):

• Fanconi anemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet
• spermatogenic failure 28

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032918155).
• BP6: Variant 14-45176512-A-G is Benign according to our data. Variant chr14-45176512-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.022 (3356/152332) while in subpopulation SAS AF = 0.0351 (169/4820). AF 95% confidence interval is 0.0308. There are 64 homozygotes in GnomAd4. There are 1655 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 64 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020937.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	NM_020937.4	MANE Select	c.3758A>G	p.Asn1253Ser	missense	Exon 14 of 23	NP_065988.1
	FANCM	NM_001308133.2		c.3680A>G	p.Asn1227Ser	missense	Exon 13 of 22	NP_001295062.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	ENST00000267430.10	TSL:1 MANE Select	c.3758A>G	p.Asn1253Ser	missense	Exon 14 of 23	ENSP00000267430.5
	FANCM	ENST00000542564.6	TSL:1	c.3680A>G	p.Asn1227Ser	missense	Exon 13 of 22	ENSP00000442493.2
	FANCM	ENST00000556250.6	TSL:1	c.3551A>G	p.Asn1184Ser	missense	Exon 13 of 22	ENSP00000452033.2

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3355 AN: 152214 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.00463

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0348

Gnomad FIN AF: 0.0499

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0250 AC: 6083 AN: 243484 AF XY: 0.0262

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.00758

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.0479

Gnomad NFE exome AF: 0.0307

Gnomad OTH exome AF: 0.0236

GnomAD4 exome AF: 0.0295 AC: 42901 AN: 1452490 Hom.: 748 Cov.: 32 AF XY: 0.0299 AC XY: 21589 AN XY: 721800

African (AFR) AF: 0.00491 AC: 162 AN: 33020

American (AMR) AF: 0.00734 AC: 320 AN: 43570

Ashkenazi Jewish (ASJ) AF: 0.0172 AC: 441 AN: 25592

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39584

South Asian (SAS) AF: 0.0360 AC: 3043 AN: 84616

European-Finnish (FIN) AF: 0.0487 AC: 2583 AN: 52994

Middle Eastern (MID) AF: 0.0149 AC: 85 AN: 5700

European-Non Finnish (NFE) AF: 0.0315 AC: 34841 AN: 1107496

Other (OTH) AF: 0.0238 AC: 1425 AN: 59918

GnomAD4 genome AF: 0.0220 AC: 3356 AN: 152332 Hom.: 64 Cov.: 32 AF XY: 0.0222 AC XY: 1655 AN XY: 74488

African (AFR) AF: 0.00462 AC: 192 AN: 41584

American (AMR) AF: 0.00960 AC: 147 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0351 AC: 169 AN: 4820

European-Finnish (FIN) AF: 0.0499 AC: 530 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0319 AC: 2168 AN: 68026

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.0282 Hom.: 226

Bravo AF: 0.0173

TwinsUK AF: 0.0275 AC: 102

ALSPAC AF: 0.0275 AC: 106

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0291 AC: 250

ExAC AF: 0.0251 AC: 3048

Asia WGS AF: 0.0140 AC: 50 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Fanconi anemia (2)
-	-	2	not provided (2)
-	-	1	Premature ovarian failure 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.058
DANN	Benign	0.29
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.20
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.029
Sift	Benign	0.40	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.097
MPC		0.069
ClinPred		0.0026	T
GERP RS		-3.9
Varity_R		0.022
gMVP		0.096
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs45604036; hg19: chr14-45645715;